!!!……Molecular Target Concept A gonist Antagonist

Toxicodynamics & Kinetics

Toxicokinetics: Disposition (ADME)  Toxicokinetics is the quantitation of the time course of toxicants in the body during the processes of absorption, distribution, biotransformation, and excretion or clearance of toxicants  In other words, toxicokinetics is a reflection of how the body handles toxicants as indicated by the plasma concentration of that xenobiotic at various time points  The end result of these toxicokinetic processes is a biologically toxic concentration of the toxicant/s

Absorption  Ability of a chemical to enter the blood stream (GI tract, skin, lungs)  Absorption: RATE & EXTENT  The rate is of toxicological importance coz is the main determinant of the peak plasma concentration  The extent determine the total body exposure or internal dose  The fraction absorbed…..bioavailability(F)  Comparing to i.v (1 or 100%)

Absorption  Route of exposure  Inhalation: readily absorb gases into the blood via the alveoli (large alveolar surface, high blood flow)  Particle size is the main determinant, ≤ 1 μ m penetrate the alveolar sacs of the lungs (nanoparticles!!)  Enteral administration: particle size, surface area, blood flow rate, pKa, intestinal motility??

Factors influencing Toxicity Oral is related to: Solid forms? Tendency to clump together Presence of food: protein and fat delay absorption, carbohydrate beverages increase absorption Chance to readily metabolize…and “hoped” detoxify!! 1 st pass effect

Absorption  Dermal: fortunately not very permeable Absorption through epidermis by passive diffusion (stratum corneum thickness, condition of skin, blood flow, small size) …..then dermis by diffusion….systemic circulation  Parenteral: I.V, I.P, I.M, S.C  Physicochemical properties of the toxicant..

Distribution  The process in which a chemical agent translocates throughout the body  Blood carries the agent to and from its site of action, storage depots, organ of transformation, and organs of elimination  Storage in adipose tissue: very lipophilic compounds (DDT) will store in fat Rapid mobilization of the fat (starvation) can rapidly increase blood concentration  Liver and kidney: high binding capacity for several chemicals  Storage in bone: chemicals analogues to calcium, fluoride, lead

Distribution: storage & binding  Rate of distribution dependent upon Blood flow Characteristics of toxicant (affinity for the tissue, and the partition coefficient)  Binding plasma proteins: in equilibrium with the free portion, displacement by another agent  Distribution may change over time

ELIMINATION = EXCRETION + METABOLISM

Elimination  Toxicants are eliminated from the body by several routes  Urinary excretion Water soluble products are filtered out of the blood by the kidney and excreted into the urine  Exhalation Volatile compound are exhaled by breathing  Biliary excretion via fecal excretion Compounds can be extracted by the liver and excreted into the bile. The bile drains into the small intestine and is eliminated in the feces  Milk, Sweat, Saliva

Metabolism (biotransformation)  Toxicity depends on the concentration of active compound at the target site over time  The process by which the administered chemical (parent compound) are modified by the organsim by enzymatic reactions  1 st objective – make chemical agents more water soluble and easier to excrete  Increase solubility ---- decrease amount at target  Increase ionization ---- increase excretion rate ---- decrease toxicity  Bioactivation/toxication ---- biotransformation can result in the formati on of reactive metabolites  When biotransformation results in metabolites of lower toxicity, the process is known as detoxification. Occasionally, biotransformation can produce an unusually reactive metabolite that may interact with cellular macromolecules (e.g., DNA). This can lead to very serious health effects such as cancer or birth defects

Metabolism (biotransformation)  Can drastically affect the rate of clearance of compounds  Can occur at any point during the compound’s journey from absorption to excretion  Key organs in biotrasnformation  Liver (principal)  Intestine,  Lung, kidney  Biotransformation pathways o Phase I: make the toxicant more water soluble o Phase II: links with a soluble endogenous agent

Factors influencing Toxicity  Poisoning do not always follow the “text-book” descriptions commonly listed for them  Signs & Symptoms that are often stated for a particular toxic episode may or may not be evident with each case of poisoning  An experimentally determined acute oral toxicity expression, such as LD50 value, is not an absolute description of the compound’s toxicity in all individuals  when evaluating a victim’s response to a toxic chemical you should keep in mind that there are numerous factors that may modify the patient’s response to the toxic agent  Those factors are the same as those which determine a drug’s pharmacologic action